The identification of regulatory T (Treg) cells as important regulators of self-tolerance has opened up new therapeutic avenues for the treatment of several human diseases associated with Treg dysfunction, including autoimmune diseases and transplantation. Recent evidence indicates that vasoactive intestinal peptide (VIP), an anti-inflammatory neuropeptide with therapeutic potential in various immune disorders, participates in maintaining immune tolerance by a novel mechanism of inducing the generation of Treg cells. We propose a Treg-cell-based immunotherapy approach for resetting the balance of immune homeostasis, which takes advantage of novel functions of VIP in immunoregulation.